Dendritic cells (DCs) are thought to play an important role in the dissemination of HIV-1 and establishment of infection. HIV subverts the normal trafficking process of DCs for its transport from mucosal surfaces to the T cell areas of draining lymphoid tissues. The proficiency of DCs in interacting with T cells makes them prime candidates for initiating and enhancing viral infection. The recent discovery that DC-SIGN, a surface receptor with high expression in DCs promotes efficient HIV infection in trans of cells that express CD4 and chemokine receptors suggests that this molecule might play a key role in DC-HIV interactions. In preliminary studies we demonstrate that plasticity of the DC-SIGN gene (designated here as DC-SIGN1), and another highly homologous gene designated as DC-SIGN2, generates a wide repertoire of DC-SIGN-like molecules. This repertoire includes potentially soluble isoforms as well as a wide array of membrane-bound DC-SIGN-like molecules that differ in their extracellular ligand (gp120) binding domain. We will test the hypothesis that DC-HIV interactions are mediated via a large class of polymorphic, but structurally-similar molecules that are generated by the alternative splicing of two distinct, but highly related genes i.e., DC-SIGN1 (original version) or DC-SIGN2. Three aims will be pursued. Aim #1 will determine the molecular repertoire and cellular distribution of DC-SIGN1 and DC-SIGN2 isoforms. Aim #2 will determine the gp120 adhesivity and HIV-1 trans-infection activity of DC-SIGN1 and DC-SIGN2 isoforms, and elucidate if naturally occurring DC-SIGN1 isoforms lacking the transmembrane domain are soluble inhibitors of HIV-1 binding to DC- SIGN1. To seek genetic evidence for a role of DC-SIGN1 in HIV-1 pathogenesis in vivo, in aim #3 we will determine the association between polymorphisms in DC-SIGN1 and risk of transmission and clinical outcome in large cohorts of HIV-infected and uninfected individuals. Our expectation is that these studies will clarify and further significantly our understanding of the role of DC-SIGN-mediated events in DC-HIV interactions in vitro, and HIV pathogenesis in vivo. They will also provide a springboard for framing new and reframing old problems related to understanding DC-HIV and DC-T cell interactions, events that play key roles in HIV pathogenesis. Our studies also place us in a unique position to pursue strategies to block DC-HIV interactions thought to be necessary for HIV transmission.